Induction of hydrogen peroxide production and Bax expression by caspase-3(-like) proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells.
In our previous studies (S. Simizu, et al., 1996, Cancer Res. 56, 4978-4982), we reported that apoptosis of human small cell lung carcinoma (SCLC) cells induced by protein tyrosine kinase inhibitors, such as erbstatin and herbimycin A, was mediated by H2O2 via a newly synthesized protein(s). In the present study, we demonstrated that induction of apoptosis by erbstatin resulted in activation of caspase-3(-like) proteases, which are interleukin-1 beta-converting enzyme family proteases (caspases) and that inhibition of these protease activities reduced the extent of cell death and H2O2 generation. We also demonstrated that expression of apoptotic protein Bax was induced by erbstatin. Erbstatin-induced Bax expression was inhibited by the inhibitor of caspase-3(-like) proteases. These results indicate that generation of intracellular H2O2 and Bax expression in tyrosine kinase inhibitor-induced apoptosis were modulated by the activation of caspase-3(-like) proteases in SCLC cells.
Simizu
S
S
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
Umezawa
K
K
Takada
M
M
Arber
N
N
Imoto
M
M
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones; D018288:Carcinoma, Small Cell; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006873:Hydroquinones / Q000494:pharmacology; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms; D009842:Oligopeptides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D011809:Quinones / Q000494:pharmacology*; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011809:Quinones; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D051028:bcl-2-Associated X Protein; D017828:Rifabutin; C020754:herbimycin; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; C048212:erbstatin